Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring.

BACKGROUND: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment. METHODS: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment. RESULTS: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data. CONCLUSION: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS.

Personalized biomarker-based treatment strategy for patients with squamous cell carcinoma of the head and neck: EORTC position and approach.

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.

Design and conduct of early clinical studies of immunotherapy agent combinations: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies.

The Methodology for the Development of Innovative Cancer Therapies task force considered aspects of the design and conduct of early studies of combinations of immunotherapy agents during their 2018 meeting. The task force defined the relevant data to justify combination clinical trials, which includes a robust hypothesis for the combination, pre-clinical data with evidence of efficacy and an understanding of the pharmacodynamics effects of each agent, and ideally evidence of single agent activity. Evaluation of pharmacodynamic biomarkers is critical in early phase combination trials, and should be incorporated into trial objectives and go/no-go decisions. The task force also identified the need to develop assessment tools and end points that capture the unique patterns of tumour responses to immunotherapy, including pseudoprogression and hyperprogression. At least one additional tumour measurement before baseline and an early CT scan (at 4 weeks for example) would help define the incidence of hyperprogression, although a common definition is needed. Finally, the task force highlighted substantial redundancy and inefficiency in the combination immunotherapy space, and recommended the adoption of innovative trial designs.

Immunohistochemical versus molecular (BluePrint and MammaPrint) subtyping of breast carcinoma. Outcome results from the EORTC 10041/BIG 3-04 MINDACT trial.

PURPOSE: This study compares immunohistochemical (IHC) versus molecular subtyping (BluePrint and MammaPrint) in the population of patients enrolled in MINDACT and outcome based on molecular subtyping (MS) versus surrogate pathological subtyping (PS) as defined by the 2013 St. Gallen guidelines. METHODS: MS classified patients in the following subtypes: Luminal A, Luminal B, HER-2-, and Basal-type. IHC/FISH for pathological subtyping (ER, PgR, HER-2, and Ki67) was centrally assessed in the European Institute of Oncology (n = 5806). Hazard ratios for distant-metastasis-free survival (DMFS) by subtype were adjusted for chemotherapy and endocrine therapy administration and thus independent of adjuvant treatment allocation. RESULTS: PS Luminal cancers classified as HER-2+ or Basal-type by MS did not have a significantly lower DMFS than the Luminal-type cancers by MS (95.9%): HR = 1.40, 95% CI 0.75-2.60 (p = 0.294). More patients were identified with Luminal A disease by MS (63%) as compared with PS (47%) with comparable 5-year DMFS (≥96.0%). Among the 500 patients with PS TN cancers, MS identified 24 (5%) patients as Luminal-type with 5-year DMFS estimated at 100% versus 71.4% for MS HER-2+ or 90.1% for MS Basal-type. CONCLUSIONS: MS was able to re-stratify 54% of patients with a Luminal-B PS subtype to a low-risk Luminal A-type group with comparable outcome. Among TN EBC, 5% were classified as Luminal by MS with Luminal-like outcome. Molecular classification can help to identify a larger group of patients with low risk of recurrence compared with the more contemporarily used classification methodology including high-quality assessed Ki67.

ESMO-Magnitude of Clinical Benefit Scale version 1.1.

BACKGROUND: The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review. METHODS: The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board. RESULTS: Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1). CONCLUSIONS: ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies.

Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study.

PURPOSE: Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC). METHODS: In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments. RESULTS: Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1-11.6) and 4.8 months (95% CI 2.8-7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9-14.8). CONCLUSIONS: CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.

ESMO - Magnitude of Clinical Benefit Scale V.1.0 questions and answers.

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a standardised, generic, validated tool to stratify the magnitude of clinical benefit that can be anticipated from anticancer therapies. The ESMO-MCBS is intended to both assist oncologists in explaining the likely benefits of a particular treatment to their patients as well as to aid public health decision makers' prioritise therapies for reimbursement. From its inception the ESMO-MCBS Working Group has invited questions and critiques to promote understanding and to address misunderstandings regarding the nuanced use of the scale, and to identify shortcomings in the scale to be addressed in future planned revisions and updates. The ESMO-MCBS V.1.0 has attracted many questions regarding its development, structure and potential applications. These questions, together with responses from the ESMO-MCBS Working Group, have been edited and collated, and are herein presented as a supplementary resource.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Tumour size is the only predictive factor of distant recurrence after pathological complete response to neoadjuvant chemotherapy in patients with large operable or locally advanced breast cancers: a sub-study of EORTC 10994/BIG 1-00 phase III trial.

PURPOSE: Although achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) in breast cancer predicts a better outcome, some patients still relapse. The objectives of this study were to describe the types of events in this group of patients and to identify predictive factors for relapse. METHODS: Patients with large operable or locally advanced breast cancers (T4d tumours were excluded) were randomised to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel followed by three cycles of eprirubicin/docetaxel. pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in the primary tumour and axillary lymph nodes at surgery. Two Cox regression analyses were performed to identify predictive factors of relapse: one for recurrence-free interval (RFI) and one for distant recurrence-free interval (DRFI). RESULTS: Out of 283 eligible patients who achieved a pCR, 40 (14.1%) and 28 (9.9%) presented an event of interest for the RFI and DRFI analyses, respectively. Five-year RFI, DRFI and overall survival (OS) were 85.3% (95% confidence interval (CI), 80.1-89.3), 89.6% (95% CI, 85.0-92.9) and 91.9% (95% CI, 87.2-94.9), respectively. No predictors for RFI after pCR were identified. For DRFI, tumour size was the only predictor: Hazard ratio (HR) T3 versus T1-2=3.62 (95% CI, 1.66-7.89); HR T4 versus T1-2: HR, 2.80 (95% CI, 0.62-12.64) p=0.0048. CONCLUSION: In this study, clinical tumour size emerged as the only predictor for DRFI after pCR, with T3 and T4 tumours having an increased risk for distant recurrence compared to T1-2 tumours.

Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper.

While they account for one-fifth of new cancer cases, rare cancers are difficult to study. A higher than average degree of uncertainty should be accommodated for clinical as well as for population-based decision making. Rules of rational decision making in conditions of uncertainty should be rigorously followed and would need widely informative clinical trials. In principle, any piece of new evidence would need to be exploited in rare cancers. Methodologies to explicitly weigh and combine all the available evidence should be refined, and the Bayesian logic can be instrumental to this end. Likewise, Bayesian-design trials may help optimize the low number of patients liable to be enrolled in clinical studies on rare cancers, as well as adaptive trials in general, with their inherent potential of flexibility when properly applied. While clinical studies are the mainstay to test hypotheses, the potential of electronic patient records should be exploited to generate new hypotheses, to create external controls for future studies (when internal controls are unpractical), to study effectiveness of new treatments in real conditions. Framework study protocols in specific rare cancers to sequentially test sets of new agents, as from the early post-phase I development stage, should be encouraged. Also the compassionate and the off-label settings should be exploited to generate new evidence, and flexible regulatory innovations such as adaptive licensing could convey new agents early to rare cancer patients, while generating evidence. Though validation of surrogate end points is problematic in rare cancers, the use of an updated notion of tumor response may be of great value in the single patient to optimize the use of therapies, all the more the new ones. Disease-based communities, involving clinicians and patients, should be regularly consulted by regulatory bodies when setting their policies on drug approval and reimbursement in specific rare cancers.

Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial.

BACKGROUND: Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. PATIENTS AND METHODS: Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. RESULTS: Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). CONCLUSIONS: pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis. CLINICALTRIALSGOV: EORTC 10994/BIG 1-00 Trial registration number NCT00017095.